Figure 2

Dysregulated pH-control systems in cancer cells. Targets for proton transport inhibitors (PTIs) as anticancer agents. Nos. 1, 2, 3, 4, 5 and 6: Mechanisms that induce intracellular alkalinisation as the key factor in cell transformation and progression with its secondary abnormalities. Secondary pH_i-dependent extracellular acidification, pH-gradient reversal and hypoxia as triggers for the metastatic process. Five targets for inhibition of proton extrusion of cancer cells as targets for metabolically-directed anticancer treatment and examples of drugs of the different proton transport inhibitors at the sites of their activity. For further details see text and ref. [5] Abbreviations: NHE1: Na⁺/H⁺ exchanger: HMA; 5-(N,N- hexamethylene)-amiloride; Phx-3: 2-aminophenoxazine-3-one; Compound 9 t: 5-aryl-4-(4-(5-methyl-1H-imidazol-4-yl) piperididn-1-yl)pyrimidine analog; HIF-1: hypoxia-inducible factor; MCT1: monocarboxylate transporter or H⁺-lactate co-transporter; CAIX: carbonic anhydrase IX; V-H⁺-ATPase: vacuolar H⁺-ATPase; VEGF: vasoendothelial growth factor; UKT-PA: urokinase-type plasminogen activator; P-gp: P-glycoprotein; MDR: multiple drug resistance; pH_i: intracellular pH; pH_e: extracellular/interstitial tumoral pH.